BACKGROUND AND OBJECTIVE: Filgrastim is a human granulocyte-colony stimulating factor (G-CSF). The biological activity of filgrastim is identical to that of endogenous G-CSF. It controls neutrophil production within the bone marrow by stimulating the proliferation, differentiation and survival of myeloid progenitor cells and some end-cell function activation. The purpose of this work is to propose a target-mediated drug disposition pharmacokinetic model of filgrastim. METHODS: A mechanism-based population pharmacokinetic model was developed to account for receptor-mediated endocytosis as a mechanism for nonlinear disposition of G-CSF. Time profiles of serum filgrastim concentrations following subcutaneous doses of 2.5, 5 and 10 microg/kg and intravenous infusion of 5 microg/kg over 0.5 hour were studied. The pharmacokinetic model included first-order elimination from the serum, receptor binding, turnover of free receptors and internalization of drug-receptor complexes. The proposed target-mediated drug disposition models served as a tool to study drug absorption and the impact of receptor binding on filgrastim clearance. RESULTS: Filgrastim was found to exhibit parallel absorption with first- and zero-order kinetics and bioavailability of 69.1%. The majority of the drug (58.6%) was absorbed by zero-order processes, presumably through the lymphatic system. The equilibrium dissociation constant (K(d)) was estimated as 16.38 pM. CONCLUSION: The proposed model predicts that clearance is initially mostly governed by the binding of filgrastim to G-CSF receptors. Subsequently, the clearance slows down because of the saturation of binding sites, and occurs mostly via the linear (renal) pathway. Finally, for G-CSF concentrations lower than the K(d), target-mediated clearance dominates. The presented receptor-mediated model adequately describes filgrastim serum concentrations and quantifies the role of receptor binding in G-CSF clearance.
BACKGROUND AND OBJECTIVE: Filgrastim is a humangranulocyte-colony stimulating factor (G-CSF). The biological activity of filgrastim is identical to that of endogenous G-CSF. It controls neutrophil production within the bone marrow by stimulating the proliferation, differentiation and survival of myeloid progenitor cells and some end-cell function activation. The purpose of this work is to propose a target-mediated drug disposition pharmacokinetic model of filgrastim. METHODS: A mechanism-based population pharmacokinetic model was developed to account for receptor-mediated endocytosis as a mechanism for nonlinear disposition of G-CSF. Time profiles of serum filgrastim concentrations following subcutaneous doses of 2.5, 5 and 10 microg/kg and intravenous infusion of 5 microg/kg over 0.5 hour were studied. The pharmacokinetic model included first-order elimination from the serum, receptor binding, turnover of free receptors and internalization of drug-receptor complexes. The proposed target-mediated drug disposition models served as a tool to study drug absorption and the impact of receptor binding on filgrastim clearance. RESULTS: Filgrastim was found to exhibit parallel absorption with first- and zero-order kinetics and bioavailability of 69.1%. The majority of the drug (58.6%) was absorbed by zero-order processes, presumably through the lymphatic system. The equilibrium dissociation constant (K(d)) was estimated as 16.38 pM. CONCLUSION: The proposed model predicts that clearance is initially mostly governed by the binding of filgrastim to G-CSF receptors. Subsequently, the clearance slows down because of the saturation of binding sites, and occurs mostly via the linear (renal) pathway. Finally, for G-CSF concentrations lower than the K(d), target-mediated clearance dominates. The presented receptor-mediated model adequately describes filgrastim serum concentrations and quantifies the role of receptor binding in G-CSF clearance.
Authors: Amita Joshi; Robert Bauer; Peter Kuebler; Mark White; Cecelia Leddy; Peter Compton; Marvin Garovoy; Paul Kwon; Patricia Walicke; Russell Dedrick Journal: J Clin Pharmacol Date: 2006-01 Impact factor: 3.126
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